Digitalis therapy



Patented 'Nov. 1, 1949 UNITED STATES PATENT OFFICE DIGITALIS THERAPY Edgar A. Ferguson, J r., Brooklyn, N. Y.

No Drawing. Application July 9, 1947, Serial No. 759,905

Claims. (01. 167-455) This invention relates generally to the art of digitalis therapy and more particularly to the production of a new and improved digitalis preparation which afiords final and complete fixation by the heart muscle of the active digitalis glycoside and which also provides for a sufiiciently slow rate of absorption and fixation so that the heart responds with maximum efficiency.

It has long been recognized that it would be desirable to administer either the full dose of digitalis, or two doses of one-half the full digitalization dose, in such a manner that both of the following conditions be fulfilled.

(1) All of the digitoxin (the active glycoside of digitalis) shall be finally absorbed and fixed by the heart muscle and (2) The rate of absorption and fixation shall be sufficiently slow that the heart will respond with maximum efi'iciency.

While the first of the foregoing conditions may now be achieved by the use of pure digitoxin the second condition is accomplished at the present time only by divided small doses. The inconvenience and possibility of error attending such administration is too well known to medical science for elaboration here.

To fully digitalize a human subject 1.2 mg. of digitoxin is usually required. It had been common practice, before the advent of digitoxin, to give this dose over a period of days while recently it has become popular to give this full digitalization dose within a period of one or two days. In certain emergency cases it is given in a few hours. There is, however, a great deal of danger in too rapid a process of digitalization.

It has now been found, in accordance with the present invention, that the foregoing and other disadvantages attending modern digitalis therapy may be obviated by providing a composition containing digitoxin, or an equivalent digitaliscontaining material, thoroughly and intimately admixed with a protective colloid so that the whole digitalization dose may be given at once or in two doses of one-half the digitalization dose each without danger of precipitation of untoward cardiac events. Stated diiierently, the present invention is predicated on the discovery that when any material containing the digitalis principle is administered with a proper amount of a protective colloid, whether administration be given intravenously, intramuscularly, subcutaneously or orally, the fixation of the digitoxin or active glycoside principle is slowed with a smoother and better controlled action so that maximum efliciency is obtained without danger of poisoning.

In order that the foregoing advantages be obtained in digitalis therapy the protective colloid employed in accordance with the invention should fulfill the following requirements:

(1) It must be soluble in water if used intravenously, intramuscularly or subcutaneously. Naturally, furthermore, it is preferable that it dissolve in water if used orally. However, if used orally it may be soluble in water containing 10% alcohol or A of 1% acetone. Likewise, it may be soluble in alcohol to form an emulsion with an aqueous mixture.

(2) It must be non-toxic.

(3) It must be only weakly acidic or basic. It may be neutral but cannot require a large amount of caustic soda content to insure its solubility.

(4) It must fulfill the requirement of a protective colloid to the extent of slowing up an approximately double dose of digitoxin.

(5) It must not completely inhibit the action of the digitoxin.

Protective colloids fulfilling the foregoing requirements and useful in the practice of the invention are water-soluble cellulose ethers such as methyl cellulose, ethyl cellulose, methyl or ethyl cellulose acetates sodium salts and carboxy methyl cellulose sodium salt. Particularly suitable is the latter salt and while the invention is obviously not limited thereto (any water-soluble cellulose ether being operative) the present description proceeds with reference to this particular compound.

Sodium carboxymethylcellulose, as its name implies, is the sodium salt of methyl cellulose in which the methyl group is substituted with a carboxyl group. It may be formulated as follows:

where m is an integer and X is O.CH2.CO2H.

Investigations by Brown and Houghton with respect to toxicity have shown the material to be harmless physiologically. The food-stuffs quality tests have shown that the lead content is less than 8 parts per million and copper and zinc each less than 1 part per million. This is a sufficiently high grade for any physiological use. For injection purposes the amount of sodium carboxymethylcellulose employed will depend upon and vary with the viscosity. When a viscosity grade of 20 centipoises per second is used a 35% solution is necessary in a concentration of .4 mg. per 0. c. of digitoxin. However, when medium viscosity grade is used, for instance 200 centipoises per second, then it is only necessary to use as little as .5% to 1%. It is obvious, therefore, that medications of any strength per 0. c. of injectable digitoxin or other digitalis-containing material may be dissolved in solutions of sodium carboxymethylcellulose in the proportion specified above, i. e., .5% according to viscosity. It will likewise be readily understood and appreciated that comparable proportions of other cellulose ethers may be employed according to viscosity.

The compositions of the present invention are suitable for any method of administration. In addition to the foregoing injectable solutions solid tablets may be prepared for oral administration. These tablets should contain the necessary dose of digitalis with sodium carboxymethylcellulose, or other water-soluble cellulose ether, making up approximately of the filler employed. Common adhesives such as gum acacia may be used as the binding material.

The following specific examples are given by Way of illustration:

Ampules Each ampule to contain 1.1 c. c. to permit Withdrawal of 1 c. 0. containing digitoxin in an amount equivalent to 1 U. S. P. Xii digitalis unit has the following ingredients: Digitoxin 0.11 mg., sodium carboxymethylcellulose (200 cps.) mg. and water 1.1 c. 0.

Tablets For a tablet containing /2 U. S. P. Xii digitalis unit the following ingredients are employed: Digitoxin .05 mg., sodium carboxymethylcellulose 100 mg. and excipients such as chalk, gum acacia, sugar to make a 5 grain size tablet.

The eflicacy of the compositions of the present invention have been demonstrated by observing characteristic electrocardiograph changes during the familiar U. S. P. Xii modification of the Hatcher-Brody method of cat-unit assay of digitalis, as well as by observing characteristic electrodiograph changes during humam assays, comparative administrations being employed involving the use of digitoxin alone, on the one hand, and digitoxin with the cellulose ether protective colloid on the other hand.

What is claimed is:

1. A composition useful in digitalis therapy comprising digitalis and a protective colloid consisting of a water-soluble cellulos ether effective in administration to afiord final and complete fixation by the heart muscle of the active digitalis glycoside while providing for a sufficiently slow rate of absorption and fixation so that the heart responds with maximum efiiciency.

2. A composition useful in digitalis therapy comprising digitalis and a protective colloid consisting of sodium carboxymethylcellulose effective in administration to afiord final and complete fixation by the heart muscle of the active digitalis glycoside while providing for a sufficiently slow rate of absorption and fixation so that the heart responds with maximum efiiciency.

3. A composition useful in digitalis therapy comprising digitoxin and a protective colloid consisting of sodium carboxymethylcellulose effective in administration to afford final and complete fixation by the heart muscle of the active digitalis glycoside while providin for a sufficiently slow rate of absorption and fixation so that the heart responds with maximum efficiency.

4. An 'injectable composition useful in digitalis therapy comprising digitoxin, sodium carboxymethylcellulose and water.

5. A composition in tablet form useful in digitalis therapy comprising digitoxin, sodium carboxymethylcellulose and at least one excipient.

EDGAR A. FERGUSON, JR.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,061,544 Bockmiihl et al. Nov. 24, 1936 2,155,658 Herrmann Apr. 25, 1939 2,156,254 Manchey Apr. 25, 1939 OTHER REFERENCES Wood-Osol: Dispensatory of U. S. 23rd ed., 1943; J. P. Lippincott Co., Phila., pages 367-373. (Copy in Division 43.)

Hollabaugh: Ind. & Eng. Chem., Oct. 1945, pages 943, 945. (Copy in P. O. S. L.)

Hueper, W. 0.: Am. J. Path. 21: 1021-1029 (Sept. 1945) (thru Aquibb Abst. Bull), vol 18, page 1281, Oct. 10, 1945. (Copy in Division 43.) 

